Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

How structural and functional MRI can inform dual-site tACS parameters: A case study in a clinical population and its pragmatic implications

BackgroundAbnormalities in frontoparietal network (FPN) were observed in many neuropsychiatric diseases including substance use disorders. A growing number of studies are using dual-site-tACS with frontoparietal synchronization to engage this network. However, a computational pathway to inform and optimize parameter space for frontoparietal synchronization is still lacking. In this case study, in a group of participants with methamphetamine use disorders, we proposed a computational pathway to extract optimal electrode montage while accounting for stimulation intensity using structural and functional MRI.MethodsSixty methamphetamine users completed an fMRI drug cue-reactivity task. Four main steps were taken to define electrode montage and adjust stimulation intensity using 4x1 high-definition (HD) electrodes for a dual-site-tACS; (1) Frontal seed was defined based on the maximum electric fields (EF) predicted by simulation of HD montage over DLPFC (F3/F4 in EEG 10–10), (2) frontal seed-to-whole brain context-dependent correlation was calculated to determine connected regions to frontal seeds, (3) center of connected cluster in parietal cortex was selected as a location for placing the second set of HD electrodes to shape the informed montage, (4) individualized head models were used to determine optimal stimulation intensity considering underlying brain structure. The informed montage was compared to montages with large electrodes and classic frontoparietal HD montages (F3-P3/F4-P4) in terms of tACS-induced EF and ROI-to-ROI task-based/resting-state connectivity.ResultsCompared to the large electrodes, HD frontoparietal montages allow for a finer control of the spatial peak fields in the main nodes of the FPN at the cost of lower maximum EF (large-pad/HD: max EF[V/m] = 0.37/0.11, number of cortical sub-regions that EF exceeds 50% of the max = 77/13). For defining stimulation targets based on EF patterns, using group-level head models compared to a single standard head model results in comparable but significantly different seed locations (6.43 mm Euclidean distance between the locations of the frontal maximum EF in standard-space). As expected, significant task-based/resting-state connections were only found between frontal-parietal locations in the informed montage. Cue-induced craving score was correlated with frontoparietal connectivity only in the informed montage (r = ?0.24). Stimulation intensity in the informed montage, and not in the classic HD montage, needs 40% reduction in the parietal site to reduce the disparity in EF between stimulation sites.ConclusionThis study provides some empirical insights to montage and dose selection in dual-site-tACS using individual brain structures and functions and proposes a computational pathway to use head models and functional MRI to define (1) optimum electrode montage for targeting FPN in a context of interest (drug-cue-reactivity) and (2) proper transcranial stimulation intensity.     

类风湿性关节炎药物治疗的进展

近年来,随着类风湿性关节炎发病机制及某些致炎因子的发现,出现了一系列新药。环氧合酶-Ⅱ特异性抑制剂与传统的非甾体类抗炎药相比具有疗效好、副作用小的优点;早期联合使用改变病情性抗风湿药在近期内有较好的临床疗效。此外重组可溶性肿瘤坏死因子受体融合蛋白 (etanercept)、人体抗肿瘤坏死因子-α单克隆抗体(adalimumab)和阿那白滞素(anakinra)等生物学治疗及中药治疗均显示了新的治疗前景。     

生物化学与细胞生物学课程整合的探讨

为了适应新世纪教学内容和课程体系改革的要求,我校借鉴美国哈佛大学医学院的经验,将生物化学与细胞生物学两门课程整合为“细胞的化学与生物学”。整合后在减少两个学科间重复内容、增加学科间联系、减少学时、早期接触临床、培养学生分析解决问题的能力、创新能力等方面有了很大改进,为这两门课程的改革开辟了新途径。     

Cytogenetic analysis in human breast tumors

Cytogenetic analysis using C-, G-, and Ag-nucleolus organizer region (NOR) staining techniques, performed on established cell lines as well as directly processed breast tumor effusions, revealed that: 1) chromosome No. 1 is involved in translocation; 2) based on 1q translocation chromosome, breast tumors could be classified into two groups; and 3) double minutes and homogeneously staining regions may be present in breast tumor cells in vivo as well as in vitro, and that homogeneously staining regions may exhibit some heterogeneity in staining.     

The role of computational models of the immune system in designing vaccination strategies

Mathematical and computational models are designed to improve our understanding of biological phenomena, to confirm/reject hypotheses, and to find points of intervention by altering the behavior of the studied systems. Here we describe the role of mathematical/computational models of the immune system. In particular, we analyze some examples of how mathematical modeling can contribute to finding optimal vaccination strategies. Indeed, computational modeling offers an intriguing opportunity from the theoretical point of view, and it will be of interest for clinically oriented investigators who wish to find optimal therapeutic strategies and for pharmaceutical industries that want to produce effective and successful drugs.     

Elastohydrodynamic separation of pleural surfaces during breathing

To examine effects of lung motion on the separation of pleural surfaces during breathing, we modeled the pleural space in two dimensions as a thin layer of fluid separating a stationary elastic solid and a sliding flat solid surface. The undeformed elastic solid contained a series of bumps, to represent tissue surface features, introducing unevenness in fluid layer thickness. We computed the extent of deformation of the solid as a function of sliding velocity, solid elastic modulus, and bump geometry (wavelength and amplitude). For physiological values of the parameters, significant deformation occurs (i.e. bumps are 'flattened') promoting less variation in fluid thickness and decreased fluid shear stress. In addition, deformation is persistent; bumps of sufficient wavelength, once deformed, require a recovery time longer than a typical breath-to-breath interval to return near their undeformed configuration. These results suggest that in the pleural space during normal breathing, separation of pleural surfaces is promoted by the reciprocating sliding of lung and chest wall.     

Experimental and theoretical models of flow during forced expiration: pressure and pressure history dependence of flow rate

Flow characteristics have been studied in elastic mono- and bialveolar lung models made from tubes and balloons in series. Flow rate variation is explained on the basis of two successive limiting factors governed by the mutual interaction of tube mechanical properties and flow characteristics, i.e. wave-speed and viscous limitations induced by the tube collapse. A numerical model of flow in an elastic monoalveolar structure has been developed. It is generally admitted that a remarkable feature of forced expiration is that the flow rate is ‘effort independent’ for approximately the lower 80 per cent of vital capacity. The present results, which describe a continuous process, suggest that the flow rate depends mostly on the external pressure and pressure history. between the 15th August 1987 and the 31st August 1988, and at other periods to him at INSERM U. 296, Faculté de Médecine, 8 av Gl Sarrail, 94010 Creteil Cedex, France.